C H A P T E R
50
Platinum*
MIRJA KIILUNEN, ANTERO AITIO, AND TIINA SANTONEN
ABSTRACT
Commercial sources of platinum are sulfide and
arsenide minerals and, increasingly, recycled plati-
num. The main source of platinum in the environ-
ment is release from vehicle catalysts, and platinum
concentrations near highways and urban areas have
gradually increased. In occupational exposure, the
form of platinum is mainly coordination complexes,
most often with chlorine as a ligand, whereas the plati-
num released from automotive catalysts is metallic or
oxidic.
The acute toxicity of platinum compounds depends
mainly on their solubility, with soluble platinum salts
being more toxic than compounds with lower solubil-
ity, such as oxides. Chloroplatinates are irritating to the
eyes and skin.
The main health effect of platinum compounds is
sensitization. Platinum salt sensitivity is manifested
as conjunctivitis, rhinitis, and asthma. The allergenic
potency of platinum compounds seems to be lim-
ited to coordination complexes containing halogen
ligands as leaving groups, with hexa- and tetrachlo-
roplatinates being the most potent sensitizers. Neutral
coordination complexes such as diamminedichloro-
platinum do not seem to be allergenic. Bromine and
iodine analogs of platinates may cause sensitization
but seem to be less potent. The mechanism of platinum
salt allergy is likely to be type 1 (i.e. involves immu-
noglobulin E). Atopic constitution is not associated
* The views presented in this chapter are those of the authors and
do not necessarily reflect the decisions or stated policies of the affili-
ated organizations.
Handbook on the Toxicology of Metals 4E
http://dx.doi.org/10.1016/B978-0-444-59453-2.00050-0
with susceptibility to platinum sensitization. Smokers
have a higher risk of platinum sensitization. No health
effects from environmental exposure to platinum have
been reported.
With the exception of platinum-containing chemo-
therapeutic drugs such as cisplatin (cis-diamminedi-
chloroplatinum), no relevant human or experimental
data are available on the potential carcinogenicity or
teratogenicity of platinum compounds. Cisplatin and
other platinum-containing chemotherapeutic drugs
are genotoxic in a variety of test systems, and other
platinum compounds have even induced mutations
in vitro (but not in vivo).
Limited data are available on the toxicity of plati-
num nanoparticles despite their increasing use in dif-
ferent applications.
Platinum compounds used as anticancer drugs such
as cisplatin and its analogs are not covered in detail in
this chapter; they are discussed only when it is infor-
mative with respect to structure-activity relationships.
1  PHYSICAL AND CHEMICAL PROPERTIES
Platinum (Pt): Chemical Abstracts Service (CAS)
number 7440-65-7; atomic mass, 195.078; atomic
number, 78; density, 21.447 g/cm3 (calculated); melt-
ing point, 1773.5 ± 1°C; boiling point, approximately
3827°C; silver-gray, lustrous, malleable, and ductile
metal, face-centered cubic; oxidation states chiefly +2
and +4, also +1, +5, and +6. Platinum is also prepared
in the form of a black powder (platinum black) and
spongy masses (platinum sponge). Six isotopes occur
naturally: 190 (0.01%), 192 (0.8%), 194 (32.9%), 195
1125 Copyright © 2015 Elsevier B.V. All rights reserved.
1126 Mirja Kiilunen, Antero Aitio, and Tiina Santonen
(33.8%), 196 (25.2%), and 198 (7.2%). The isotope 190
is radioactive with a half-life of 6.9 × 1011 years. Artifi-
cial radioactive isotopes include 173-189, 191, 193, 197,
199-201.
Platinum is unaffected by air at any temperature. It
reacts with boiling aqua regia (with the formation of
chloroplatinic acid) and with molten alkali cyanides.
Halogens, cyanides, sulfur, molten sulfur compounds,
and hydroxides can affect platinum.
The most important platinum compounds are those
with halogens. The binary compounds are chlorides
(+2 and +4), the oxide, and the sulfate and nitrate.
Tetravalent platinum compounds are readily soluble
in water, except for platinic oxide, which is soluble in
dilute phosphoric acid and other concentrated acids,
and is easily soluble in dilute potassium hydroxide
solutions. Divalent platinum chloride is insoluble in
water, alcohol, and ether but soluble in hydrochloric
acid (HSE, 1996).
In chloride-containing aqueous solutions, the coor-
dination complex compounds hexachloroplatinic
and tetrachloroplatinic acids, and their alkali salts
are the dominant platinum species (over platinum
chlorides).
Certain platinum coordination complexes with dif-
ferent ligands [cisplatin (cis-diamminedichloroplatinum
(II)], carboplatin, (cis-diammine(1,1-cyclobuta­
nedicarboxylato)platinum(II), oxaliplatin, trans-1R,2R-
diaminocyclohexaneoxalatoplatinum(II), nedaplatin
(diammine[(hydroxy-κO)acetato(2-)-κO]platinum), loba-
platin (1,2-diammino-methylcyclobutane-platinum (II)
lactate), heptaplatin [SP-4-2-[4R-(2a,4a,5b)]]-[2-
(1-methylethyl)-1,3-dioxolane-4,5-dimethanamine-
N,Nʹ][propanedioato(2-)-O,Oʹ]-platinum, mirip-
latin (SP-4-2-[(1R,2R)-cyclohexane-1,2-diamine-N,Nʹ]
bis-(tetradecanoate-O) platinum) are used in cancer
chemotherapy. Of the two stereoisomers of diam-
monium chloroplatinate [cis- and trans-diamminedi-
chloroplatinum (II)], only the cis-form is effective as a
chemotherapeutic.
2  METHODS AND PROBLEMS OF
ANALYSIS
Several methods are available to determine plati-
num levels in biological materials. Initially, electrother-
mal atomic absorption and adsorptive voltammetric
methods were mainly used: their detection limits are
low enough for studying the body fluids of patients
who were treated with drugs, but for environmental
exposure more reliable methods are needed. Induc-
tively coupled plasma mass spectrometry (ICP-MS),
sector field ICP-MS (SF-ICP-MS), neutron activation
analysis (NAA), and modern adsorptive voltammetry
are sensitive enough and are widely used techniques
for the determination of platinum at nanogram and
sub-nanogram levels in a wide variety of biological and
environmental matrices. The most sensitive method is
adsorptive voltammetry, with a limit of quantification
of few picograms per grams. In addition, chromato-
graphic methods have been developed for urine, with
detection limits of 1.8 ng/L and 1.6 ng/L (Hu et al.,
2005; Li et al., 2006). Limits of quantification of 50 pg/L
for urine, 10 pg/L for plasma, and 5 pg/L for plasma
ultrafiltrate were recently reported for electrothermal
atomic absorption methods (Vouillamoz-Lorenz et al.,
2001). In a comparison of SF-ICP-MS with adsorptive
cathodic stripping voltammetry at ultratrace levels of
platinum in biological samples, identical results were
obtained with both methods, but voltammetry was 20
times more sensitive than SF-ICP-MS (Renner et al.,
2002; Zimmermann et al., 2001) and approximately
6000 times more sensitive than the standard flameless
atomic absorption spectrophotometry (AAS) method
(Gelevert et al., 2001). In a comparison of different ICP-
MS techniques for urine specimens, the detection limit
with SF-ICP-MS was 0.05 ng/L and with a quadruple
instrument was 0.18 ng/L, taking into account dilution
factors (Spezia et al., 2005). The lowest platinum con-
centrations measured in tissue samples were approxi-
mately 200 ng/kg, analyzed with SF-ICP-MS. X-rays
have also been exploited for tissue analysis (Tay-
lor et al., 2002). After ultraviolet irradiation of urine
samples, platinum was determined by SF-ICP-MS at
the level of 1000 pg/L, with an absolute detection of
30 pg/L (Caroli et al., 2001). Microwave digestion of
plasma and ultrafiltration of plasma as pretreatment
was performed using the “hot plasma” mode of ICP-
MS determination of platinum, with a detection limit
of 0.9  ng/L and a quantification limit of 1.9  ng/L
(Breda et al., 2008). A detection limit of 0.9 ng/L in
human urine was achieved with an online sample
clean-up/preconcentration step using a chelating resin
prior to ICP-MS determination (Lopes et al., 2007). An
ultrasonic nebulizer connected to SF-ICP-MS has been
used for plasma and whole blood samples (Morrison
et al., 2000). For the accurate determination of plati-
num by ICP-MS, correction by the use of interference
equations is needed to prevent the molecular ion and
doubly charged ion interferences induced by CuAr+,
HfO+, SrO+, YO+, and Pb2+.
Because of the need for detection at the nanogram
level, preconcentration methods are required in many
cases.
With improved analytical methods, some of the pre-
viously reported concentrations have been shown to
be in error. There is a lack of useful control materials
 50 Platinum
at required concentration levels and matrices. Inter-
national quality assurance schemes are available for
­biological materials (in Germany and in Canada).
3  PRODUCTION AND USES
3.1 Production
Platinum is mainly found in sulfide and arsenide
minerals as sperrylite PtAs2, cooperite (Pt,Pd)S, and
braggite (Pt,Pd,Ni)S; it usually occurs together with
other platinum group metals (PGMs). The main depos-
its are in the Republic of South Africa, Russia, the
United States, and Canada. The world production of
platinum in 2011 was 184 tons. Demand for platinum
in 2010 was 230 tons and recycling increased by 12% to
58 tons. (Butler, J., 2012).
Sulfite and arsenide ores are first smelted to pro-
duce a metal sulfide mixture. Other metals are then
precipitated from the mixture; selenium, tellurium,
and sulfide are removed from the concentrate of pre-
cious metals. Silver and gold are separated electrolyti-
cally, with liquid extraction or precipitation from the
chlorinated solution. The PGMs are precipitated and
refined using different techniques (Renner et al., 2002).
3.2 Uses
The major industrial users of platinum are the
automotive, electronic, chemical, jewelry, dental, and
glass industries. Platinum has wide-ranging catalytic
qualities. For example, it is used in catalytic convert-
ers in car exhaust systems. The automotive indus-
try accounts for approximately 80% of platinum use
(Matthey, 2004; Renner et al., 2002). Platinum use in
this sector has been largely offset by the continuing
substitution of platinum by palladium (Butler, 2012).
The platinum emission rate has been estimated to be
0.5-0.8 μg Pt/km from traffic (Pyrzynska, 2000). The
second largest consumer is the chemical industry.
Platinum is used as a catalyst in hydrogenation, dehy-
drogenation, and isomerization reactions; in the man-
ufacturing of paints, acids, fertilizers, and explosives;
and in oil refining. In the dental industry, platinum is
used in the construction of crowns, bridges, pins, and
other dental equipment, as well as in fillings, and its
use is expected to increase in the future. Demand for
platinum in medical applications, including the den-
tal industry, is forecast to be 7200 kg in 2010 (Butler
2010). The jewelry industry uses platinum as “white
gold” because its strength and luster makes it an ideal
setting for diamonds; however, the use in jewelry has
decreased in the past decade. The electronics industry
uses platinum in liquid crystal display lights, picture
1127
tubes, and fiber optic cables. This use increased 44%
during 2011 to almost 16 tons (Butler, 2012). Platinum-
based fuel technology is being promoted as the best
option for electric cars (Matthey, 2004; Renner et al.,
2002).
Platinum has been used in noble metal-ceramic
alloys in dentistry, but its use has decreased as other
materials with better mechanical properties and sag
resistance have become available (Roberts et al., 2009).
Parenteral exposure to platinum may be caused by
the use of platinum as a catalyst to accelerate the trans-
formation of silicone oil into silicone gel for making elas-
tomer silicone shells and other medical silicone devices
such as breast implants (Rinzler 2009, IM-CSSBI 1999).
Recent advances in nanotechnology have enabled
the development of various metal nanoparticles,
including platinum nanoparticles (PNPs). PNPs
have greater catalytic activity than larger platinum
particles; therefore, they are of especial interest for
catalytic applications. In addition, PNPs have been
proposed as a material with a potential use in can-
cer therapy (Porcel et al., 2010). Some modified PNPs
have been shown to have antioxidant properties and
have therefore found uses in cosmetics and as food
additives.
4  ENVIRONMENTAL LEVELS AND
EXPOSURE
4.1  General Environment
Earlier studies indicated that the platinum concen-
tration in the Earth’s crust is 1-5 μg/kg (IPCS, 1991);
a more recent study reported an average concentra-
tion of 2.7 μg/kg (Tereshima et al., 2002). The primary
anthropogenic source of platinum in the environment
is its use in catalytic converters in cars (Wiseman and
Zereini, 2009; IPCS 1991).
Limited data are available on platinum concentra-
tions in the air in rural areas. Before the introduction
of cars with catalytic converters, the values near free-
ways in the United States were below the detection
limit of 0.05 pg/m3 (Johnson et al., 1975, 1976). Plati-
num concentrations in exhaust fumes were between
33.2-313.4 ng/km (mean of soluble form, 1.6 ng/km)
collected from a new gasoline car fitted with a Pt-Pd-
Rh catalyst. After 30,000 km, used platinum concentra-
tions in exhaust fumes were stabilized to 2.0-22.1 ng/
km (mean soluble form, 0.5 ng/km) (Moldovan et al.,
2002). During the 1980s in Japan, the values were
0.014-0.184 μg/g of dust (Mukai et al., 1990). In 2000,
the reported platinum background concentrations in
Germany were < 4 pg/m3 (Merget and Rosner, 2001);
1128 Mirja Kiilunen, Antero Aitio, and Tiina Santonen
they are currently 2.0 pg/m3 (0.1-80.9 pg/m3) (Zereini
et al., 2012).
In urban areas, the reported concentrations of plati-
num in the air were between 0.9 and 147 pg/m3 in the
2000s, and a trend toward a continuous increase in the
ambient concentration of platinum was also noted in
the 2010s (Bocca et al., 2006, Caroli et al., 2001; Gómez
et al., 2001, 2003; Kanitsar et al., 2003; Petrucci et al.,
2000; Probst et al., 2001; Rauch et al., 2001; Schierl,
2000, 2001; Zereini et al., 2001a,b; Rauch et al., 2006;
­Wichmann et al., 2007). Between 1988 and 1998, there
was a 46-fold increased level of platinum in the ambi-
ent air and dust (Zereini et al., 2001a), and between
1994 and 2004 the increase in dust was still as high as
twofold in Germany (Zereini et al., 2007); concentra-
tions were dependent on traffic density and driving
speed (Gao et al., 2012; Gómez et al., 2001; Pan et al.,
2009). The highest average platinum concentrations
are found in the particulate matter of ≤ 2.5μm diam-
eter (PM-2.5) fraction, from 4.3 pg/m3 to 9.4 pg/m3
(­Kanitsar et al., 2003; Zereini et al., 2012), and was
observed to decline with the size of particle fraction,
from PM10 to PM1.0 (Zereini et al., 2012).
Platinum concentration in ice from Greenland dat-
ing back 7000 years was 8 pg/kg, and in snow from
Greenland, Antarctica, and the Alps ranged from 8 to
2700 pg/kg (Barbante et al., 1999). A 50-year record of
platinum in East Antarctica snow showed an average
platinum concentration of 17 pg/kg. Concentration
peaks for Pt were observed at depths corresponding to
volcanic eruption periods and after the 1980s (Soyol-
Erdene et al., 2011). In fresh snow in 2003-2004 from
the Pyrenees Mountains in France the platinum con-
centration ranged from 0.20 to 2.51 pg/kg (Moldovan
et al., 2007). In water from the Pacific Ocean, platinum
concentrations were 90-228  pg/L (Goldberg et al.,
1986); in the Indian Ocean, they were 33.2 pg/L (van
der Berg and Jacinto, 1988). Similar concentrations
have been reported off the coast of Australia (Adeloju
et al., 1990). Clearly higher concentrations of platinum
(2.6-4.4 ng/L) were reported from fountains in Spain
(Moldovan et al., 2003). The International Atomic
Energy Agency (IAEA, 2005) measured platinum con-
tent in seawater to be 0.3-2.4 ng/L and in river water
in the Elbe in 1991 to be 0.8-7 ng/L dissolved and ≤ 0.2-
0.8 ng/L as particulates. Platinum concentrations in
river water (Mvudi, Madanzhe) in South Africa var-
ied from not detected to 10.4 μg/L and in river water
mixed with sewage from 5.5 μg/L to 34.6 μg/L (Odiyo
et al., 2005). In China the level was 52.5 ng/L (Hu et al.,
2005). In a single sample of tap water in Liverpool, the
platinum concentration was 60 pg/L (van der Berg
and Jacinto, 1988) and in Victoria in Australia it was
< 100 pg/L (Adeloju et al., 1990). The IAEA (2005) has
given a value of 0.1 ng/L for tap water and 0.2-0.8 ng/L
for rainwater. In rainwater, platinum concentrations
were < 0.2 pg/kg in the 1990s in Germany (Alt et al.,
1997) and 34.4 pg/L in South Korea in 2008 (Soyol-
Erdene et al., 2008).
In sediments from the central Pacific Ocean, plati-
num concentrations were on average 8.6 μg/kg; near
the Japan coast, sediments contained 2.3 μg/kg; and
in lake sediments from Japan, they were 3.2 μg/kg
(Tereshima et al., 2002). In the Ruhr district of Ger-
many, the platinum content in sediment varied from
< 0.36 μg/kg to 4.9 μg/kg (Haus et al., 2007). In China,
platinum concentrations in uncontaminated soils were
0.20-0.33 μg/kg (Qi et al., 2011). In Sweden, the plati-
num content in urban river sediment averaged 53.2
and 54.6 ng/g dry weight at different sampling points
(Moldovan et al., 2001). In Italy, the platinum content in
soil from a nature reserve was 2.51 ng/g; at an agricul-
tural site, 2.78 ng/g; in a suburban area, 63.3 ng/g; and
in an urban area, 73.3 ng/g dry weight (­Marcheselli
et al., 2010).
The IAEA’s (2005) values for soil are 30-260 pg/g for
uncultivated, 150-3900 pg/g for cultivated, and 1560-
31700 pg/g for highways.
Platinum usually occurs together with small quan-
tities of iridium, osmium, palladium, ruthenium, and
rhodium in alluvial deposits, where platinum concen-
trations of 10 μg/kg have been reported. The median
content of platinum in a peat bog was 5 μg/kg (Rauch
et al., 2004) and in garden soil was 0.15-3.9 μg/kg (Alt
et al., 1997; Hutchinson et al., 2000).
A clear increase in platinum concentration has been
noticed in roadside dust and soil up to the order of
300 μg/kg (mean value), with highest concentrations
of > 2250 μg/kg (Ravindra et al., 2004). In Beijing,
37-fold higher concentrations on average (56.2 μg/kg
dust) were reported in high-density traffic area com-
pared to low-density park areas (6.9 μg/kg dust) (Gao
et al., 2012). The highest platinum concentrations were
found in incinerator ash (mean, 190 μg/kg), in inciner-
ator ash in landfill (mean, 107 μg/kg), and in road dust
(146 μg/kg) in Sheffield in the UK (Jackson et al., 2007).
The deposition rate of platinum from catalysts is
estimated to be 5 μg/m2/year on the road surface and
2.2-6.2 μg/m2/year at the roadside (within 2 m) (Rauch
et al., 2005). High platinum levels in road dust were
found at sites of erratic stop-start driving conditions:
e.g. 178 ng/g platinum in road dust around a vehicle
crossing gate. The existence of Pt-containing PM in the
atmosphere was observed as elevated platinum levels
in tree bark (0.9-4.5 ng/g) (Lee et al., 2012).
The mean concentration in grass has increased from
3.4 ng/g in 1995 (Helmers et al., 1998) to 8.63 ng/g in
Poland (Leśniewska et al., 2004) and 8.25 ng/g (dry
 50 Platinum
weight) in the UK in 2000 (Hooda et al., 2007). In Tierra
del Fuego National Park in Argentina, the baseline plati-
num concentration in lichens was 0.0016-2.735 μg/kg
dry weight in 2006 ( Pino et al., 2010).
Platinum concentrations in crustacean species in
the Ruhr area in Germany 0.5-1.3 μg/kg wet weight
(Haus et al., 2007); in waterlice (Asellus aquaticus) col-
lected in an urban area of Göteborg, Sweden, were
38.0 ± 34.6 ng/g dry weight (Moldovan et al., 2001);
and in tissues of mussels from Austria were < 20 μg/
kg (Zimmermann et al., 2005b). In mussels, the uptake
of platinum from catalyst dust-polluted humic water
(4300 μg/kg) was greater than the uptake from unchlo-
rinated tap water (< 780 μg/kg) over a period of 18
days (Zimmermann et al., 2005b).
In Italy, platinum concentrations were studied in
wood mice (Apodemus sylvaticus) living in a nature
reserve, 3 km from an urban area (control), in an agri-
cultural site, in the suburban area of the city, and in an
urban area in the vicinity of a traffic (approximately
7000 vehicles/day). The platinum content in mouse
liver and hair was ∼1 ng/g dry weight in control and
agricultural areas, below 3 ng/g in suburban area and
over 3 ng/g in urban area (all dry weights). The con-
centrations in the kidneys were 2 ng/g, 7 ng/g and
9 ng/g dry weights respectively (Marcheselli et al.,
2010).
Laboratory tests have shown the uptake of platinum
by the water louse A. aquaticus (Moldovan et al., 2001)
from river soil, by the zebra mussel (Dreissena polymor-
pha) from road dust (Zimmermann et al., 2002), by the
marine gastropod Littorina littorea from contaminated
marine water (Mulholland and Turner, 2011), and by
European eels and its parasites from ground catalytic
converter material (Zimmermann et al., 2005a), as well
as the solubility of platinum from aerosol particles in
synthetic gastric juice (Puls et al., 2012).
In 2005, the IAEA published a list of platinum lev-
els in various materials: elderberry leaves next to a
highway, 800-2500 pg/g; poplar leaves (Andes, Chile),
40 pg/g; spruce shoots, 100-550 pg/g; and gasoline
0.15-5.2 ng/L.
4.2  Working Environment
Occupational exposure to platinum occurs mainly
through inhalation during mining, manufacturing,
and processing different platinum compounds, and by
people who are exposed to traffic dust in their work.
The most common current occupational exposure to
soluble platinum compounds is in platinum refining
and catalyst manufacture (IPCS, 1991). The results of
studies on occupational exposure that are considered
reliable are presented in Table 1.
1129
4.3 Food
In Germany in 1997, platinum concentrations were
0.31 μg/kg dry weight in peeled potatoes, 0.04 μg/kg
in grain products, and 0.31-2.1 μg/kg in fruits and veg-
etables (Alt et al., 1997). Platinum concentrations in rice
on the Swedish market were < 0.3 μg/kg in 2001-2003
(Jorhem et al., 2008). In Italy in the 2000s, platinum
concentrations were 17 ng/kg dry weight in vegetables
and 93 ng/kg in flour products (Frazzoli et al., 2007).
The total platinum intake in the diet was reported to
be 0.02 μg/day in the UK in 1994 (Ysart et al., 1999); in
2006 it was 0-0.0023 mg/day, and the estimated intake
was 0-0.029 μg/kg body weight/day (Rose et al., 2010).
In Ghana in the 2010s, platinum concentrations in fish
were on average: Tilapia spp., 0.019-0.113 μg/g dry
weight; Brown Goby, 0.016-0.017 μg/g dry weight;
shrimps, 0.100 μg/g dry weight; and oysters, 0.006-
0.088 μg/g dry weight (Essumang et al., 2010).
According to the IAEA (2005), the average platinum
concentrations are: peeled potatoes, 100 pg/g; salad,
2100 pg/g; flour, ≤ 40 pg/g; wine, < 0.4-2.4 ng/L; honey,
< 2 pg/g; and Brussels sprouts grown within 100 m of a
highway, 250 pg/g.
5  KINETICS AND METABOLISM
5.1  Absorption, Distribution, and Excretion
In vitro, there was a slow release (< 0.4% in 700 h) of
platinum into simulated interstitial fluid of the lungs,
but a considerably faster release (up to 36% in 700 h)
into artificial lysosomal fluid (pH 4.5) from standard
reference material of road dust, recycled autocatalyst,
or synthetic Pt(OH)2 (Colombo et al., 2008a).
After inhalation exposure of rats to metallic plati-
num, platinum oxide, platinum tetrachloride, and plat-
inum sulfate (191Pt; aerodynamic droplet size of nearly
1.0 μm), the bulk of the radioactivity was excreted in
the feces within 2–3 days. Thereafter, there was slow
excretion in both the feces and urine. The second phase
was relatively fast for Pt(SO4)2, with pulmonary reten-
tion being 4.4% after 16 days, but was slow for metal-
lic Pt and PtO (17.9 and 28.0% retention) (Moore et al.,
1975a). After endotracheal instillation of metallic plati-
num on aluminum oxide particles (a model aerosol for
automobile exhaust), Al2O3 particles of ≤5 μm coated
with ≥ 4-nm platinum particles), approximately 97%
of the dose was excreted in the feces within the first
2 days (Artelt et al., 1998). After day 5, urinary excre-
tion accounted for approximately 5% of the total daily
excretion.
Release of platinum from road dust during in vitro
simulated passage through the acid environment in
1130 Mirja Kiilunen, Antero Aitio, and Tiina Santonen

TABLE 1  Platinum Exposure in Different Industries

Time of No. and Type Parameter
­Sampling Exposure Group of Samplesa ­Measuredb Result, Average Reference

Refinery

1977–1979 Residue 1; area Total dust 0.5 μg/m3 Baker et al., 1990

Recovery 9; area Total dust 5.3 μg/m3
Recovery, sampling 4; area Total dust 2.7 μg/m3
Refinery 3; area Total dust 10.7 μg/m3
Refinery, tray room 4; area Total dust 27.1 μg/m3
Analytical laboratories 3; area Total dust 0.4 μg/m3
Warehouse 8; area Total dust 8.6 μg/m3
Air conditioning unit 3; area Total dust 0.6 μg/m3
1981 Refinery, recovery, warehouse area 75, area Total dust 50-70%, ≥ 2 μg/m3 Brooks et al.,
1990
1984 Platinum-processing department 2; area Total dust < 0.2 μg/m3 (detection limit) Bolm-Audorff
et al., 1992
1986 Platinum-processing department 2; area Total dust 0.08 μg/m3, 0.1 μg/m3
Filter press 2; personal < 0.05 μg/m3 (detection limit)
1986 Maintenance, incinerator 566 Total dust 27%, > 2 μg/m3 Calverley et al.,
1995
Security, canteen and cleaning, mes- 45 All < 2 μg/m3
sengers, medical centra, laborato-
ries, boilerhouse, changehouse
1976–1995 PGM refinery 8573; area, Total dust, soluble 5.1%, ≥ 2 μg/m3; maximum, Linnett and
personal platinum 234 μg/m3 Hughes, 1999
1989–1991 Chemical process operators in 380; area, Total dust; soluble 2.4% > 2 μg/m3
PGM refinery personal platinum
Refining platinum 35 Respirable soluble Long-term sampling, 0.663 μg/ Maynard et al.,
platinum m3; maximum, 2.210 μg/m3 1997
Short-term sampling, 2.53 μg/
m3; maximum, 725.96 μg/m3
1989–2006 Petroleum refining industry 67, area, Total dust, soluble Catalyst-unloading area, < 7 μg/ Lewis et al., 2012
­personal platinum m3; personal, < 20 μg/m3
Catalyst-loading area, < 3 μg/
m3, personal, < 6 μg/m3
Manufacturing of platinum chemicals

1976–1995 TPC production 511; area, Total dust, soluble 48.3 ≥ 2 μg/m3; maximum, Linnett and
personal platinum 6500 μg/m3 Hughes, 1999
1989–1991 Chemical process operators in 130; area, Total dust; soluble 28.5%, > 2 μg/m3
TPC production personal platinum
Catalyst production

1992–1993 56; area Total dust, soluble Low-exposure areac Merget et al.,
platinum 1992: 0.003-0.010 μg/m3 2000
1993: < 0.002 μg/m3
High-exposure areac
1992: 0.005-0.6 μg/m3
1993: 0.006-0.1 μg/m3
22, personal Soluble salts, < 0.01 μg/m3
total Pt < 0.085 μg/m3
1976–1995 Autocat 453; area, Total dust, soluble 28.7%, ≥ 2 μg/m3; Linnett and
personal platinum maximum, 438 μg/m3 Hughes, 1999
1989–1991 Chemical process operators in 176; area, Total dust; soluble 8.5%, > 2 μg/m3
Autocat personal platinum
Platinum catalyst production 35 Respirable soluble Long-term sampling Maynard et al.,
platinum 0.216 μg/m3; maximum, 1997
0.600 μg/m3
Short-term sampling
0.975 μg/m3; maximum,
10.82 μg/m3
 50 Platinum 1131

TABLE 1  Platinum Exposure in Different Industries (—Cont’d)

Time of No. and Type Parameter

­Sampling Exposure Group of Samplesa ­Measuredb Result, Average Reference

Preparation of solutions for coating 3,2,2 area, Soluble PM10/total/ 0.02/0.08/0.02 μg/m3 Petrucci et al.,
PM10 soluble platinum 2004, 2005
Coating of supports for catalytic 8, 3,3 area, 1.71/2.54/0.67 μg/m3
converters PM10
Adsorption on the carrier 4,2,2 area 0.24/0.34/0.08 μg/m3
PM10
Recovery of PGMs from exhausted 2,2,2, area, 0.18/0.42/0.03 μg/m3
catalytic converters PM10
Preparation of solutions for coating 3, personal Total, soluble plati- 0.41 μg/m3 Petrucci et al.,
num 2005
Coating of supports for catalytic 7, personal 2.70 μg/m3
converters
Adsorption on the carrier 5, personal 0.05 μg/m3
Recovery of PGMs from exhausted 2, personal 0.68 μg/m3
catalytic converters
Refinery and catalyst production

?, area 1.1 μg/m3; maximum, 3.4 μg/m3 Schierl et al., 1998

34, personal 2.5 μg/m3; maximum, 7.5 μg/m3
Metal coating

Metal-coated electrodes 32 Respirable soluble Long-term sampling, 0.017 μg/ Maynard et al.,

Metal-coated electrodes
paint mixing
Hospital chemotherapy
platinum m3; maximum, 0.079 μg/m3 1997
Short-term sampling, < 0.03 μg/
m3; maximum, 0.99 μg/m3
6 Respirable soluble Short-term sampling, 0.36 μg/ Maynard et al.,
platinum m3; maximum, 1.10 μg/m3 1997

Heated intraperitoneal perioperative 3, area Soluble Not detected, 0.014 ng/m3 and Konate et al.,
chemotherapy 0.059 ng/m3 2011

Autocat, autocatalyst production; PGM, platinum group metal; TPC, tetraammine platinum dichloride.
aMedian values taken from a logarithmic diagram.
bPM , the average particle size below 10 μm.
10
cEstimated from graph.

the stomach to the neutral environment of the small
intestine reached 15%, while that from recycled auto-
catalyst and synthetic Pt(OH)2 was approximately
0.1% and 0.01%, respectively (Colombo et al., 2008b).
Three days after an oral dose of 191platinum(IV)
chloride, the whole body retention of radioactivity
was < 1% of the dose in both adult and suckling rats,
indicating very limited oral absorption (Moore et al.,
1975b). A similar low level of absorption was observed
after an oral dose of Pt(SO4)2 at dose levels correspond-
ing to the lethal dosage for 5% (LD5) and LD25 (Lown
et al., 1980). No platinum could be detected in any
organ after the dietary administration of PtO2 to rats,
indicating that the absorption was < 3% of that of PtCl4
(Holbrook, 1977). After oral exposure to the model
particulates for automotive exhaust gases (described
above) containing metallic platinum, 0.11% of the plat-
inum administered was absorbed (Artelt et al., 1999).
After intravenous administration to rats of PtCl4 or
metallic Pt by inhalation, the highest concentrations
were observed in the kidney (Moore et al., 1975b,c).
Similarly, after the endotracheal instillation, inhala-
tion, or oral administration of metallic platinum on
aluminum oxide particles to rats (Artelt et al., 1998,
1999) and the dietary administration of Pt(SO4)2 to
mice (Lown et al., 1980), the highest Pt concentrations
were observed in the kidney. Concentrations similar to
or higher than those in the blood were also observed in
the adrenal glands, spleen, liver, and bone (Artelt et al.,
1998, 1999; Lown et al., 1980; Moore et al., 1975b,c).
Following an intravenous dose of 191platinum chlo-
ride administered to rats, radioactivity in the testis at
1-14 days was 18-33% of that in the blood (Moore et al.,
1975b).
Platinum crosses rat placenta in limited amounts
only: after a single oral dose of 191platinum in hydrogen
1132 Mirja Kiilunen, Antero Aitio, and Tiina Santonen
chloride to pregnant rats on day 18 of gestation, radio-
activity in the fetal liver was 0.77% of that in the liver
of the dam. Most of the platinum was retained by the
placenta and did not reach the fetus: the concentration
in the placenta was 65 times the average concentration
in the fetus (Moore et al., 1975b).
In plasma, 90% of platinum is bound to proteins
(Artelt et al., 1999). After intravenous administration
of potassium chloroplatinite (K2PtCl4) to rats, approxi-
mately 50% of the dose was excreted in the urine and
41% in the feces (Artelt et al., 1999).
In a single case of attempted suicide, a 31-year-old
man ingested 10 mL of a photographic toning solution
containing 600 mg K2PtCl4. Subsequent toxic effects
included acute oliguric renal failure, metabolic acido-
sis, fever, muscle cramps, gastroenteritis, and rhab-
domyolysis. Abnormal laboratory findings included
mildly elevated liver enzymes and blood neutrophil
and eosinophil counts. All signs and symptoms of tox-
icity resolved within 6 days with supportive medical
management. The spot serum platinum concentration
was 24.5 μg/L and the spot urine platinum concentra-
tion was 4200 μg/L. (Woolf and Ebert, 1991)
In two human volunteers exposed for 4 h by inhala-
tion to (NH4)2PtCl4, urinary excretion of platinum had
increased steeply (15-1000-fold compared with initial
values) in the first urine samples after exposure. Plati-
num excretion followed a biphasic exponential decay
pattern, with a first half-time of 50 h [95% confidence
interval (CI), 36-66 h]. The second half-time was 24
days (95% CI, 18-33 days). A total of 167 days after
exposure, the urinary platinum concentration was
greater than the concentration before exposure, but
was within values observed for unexposed individu-
als (Schierl et al., 1998).
The absorption and elimination of diammine com-
plexes of platinum, such as cisplatin and its analogs, is
quite different from those of inorganic platinum salts
(Beauchamp Hewitt, 1997). The excretion of antineo-
plastic platinum drugs follows a biphasic pattern. The
half-time of ultrafiltrable platinum in plasma (131 ± 15
min) was much faster than that of total platinum
(6.8 ± 4.3 days) after exposure to cisplatin and lobapla-
tin (Nygren and Lundgren, 1997; Welink et al., 1999).
The rapid initial phase accounts for the early high
levels of platinum in the kidney, and the prolonged
second phase results in detectable urine platinum con-
centrations 30 days after a single dose (IPCS, 1991).
After four cisplatin treatments, the mean half-time in
serum was 7.5 days (Gamelin et al., 1995).
There is limited information available on the toxi-
cokinetics of PNPs. Oral administration of PNPs (with
size of 20 nm) to mice during premating, gestation,
and lactation periods resulted in the dose-dependent
accumulation of platinum in the lungs of the dams; no
accumulation was observed in the liver and kidneys.
In addition, fetal levels remained below detection lim-
its, suggesting a low ability of PNPs to cross the pla-
centa (Park et al., 2010a).
5.2  Reference Values in Tissues and Biological
Fluids
As discussed previously, earlier studies tend to
report high concentrations of platinum in biological
fluids. In the following section, only studies consid-
ered analytically reliable and comprising a reasonable
number of study subjects have been discussed.
Dental gold alloys were found to increase urinary
and saliva platinum concentrations [326 urine samples
from 92 individuals; median 9.3 ng/g creatinine with
dental gold inlays (50 individuals; mean age, 35.9 years)
and 5.3 ng/g creatinine without dental inlays (42 indi-
viduals; mean age, 34.3 years), P < 0.001] and [55 saliva
samples; 5-2770 pg/g saliva, median 160 pg/g with
any dental gold alloy (n = 20) and 4.8-26 pg/g saliva,
median 8.1 pg/g saliva without dental alloys (n = 35),
P < 0.001] (Schierl, 2001). The German Environmental
Survey (GerES III) from 1998 (Becker et al., 2003) found
a positive relation between platinum levels in urine
and teeth with dental inlays, crowns, and bridge ele-
ments; the amount of road traffic was also related to
urinary platinum concentrations. The geometric mean
value for all occupationally unexposed persons (age,
18-69 years; n = 1080) was 2.18 ng/L (1-75 ng/g creati-
nine), and the 95% CI from the log-normal distribution
was 2.01-2.36 ng/L (1.60-1.90 ng/g creatinine). Those
with no dental inlays (n = 509) had a geometric mean
platinum concentration in urine 1.32 ng/L (0.99 ng/g
creatinine), with a 95% CI of 1.1-1.47  ng/L (0.89-
1.11 ng/g creatinine). From the same study, ­Benemann
et al., (2005) found that the daily consumption of chew-
ing gum intensified the release of platinum from noble
metal dental alloy restorations associated with a 6.9%
increased platinum burden, with a median value of
4.45 ng/L. In Germany, a new reference value in urine
was set at 0.01 μg/L in 2004 (Wilhelm et al., 2007).
This applies to adults (18-69 years) without dental
inlays, crowns, bridge elements of precious metals in
their teeth (Becker et al., 2003). In a population study
(National Health and Nutrition Examination Survey)
in the United States, the 95th percentile of urinary plati-
num concentrations in 2009-2010 was 16 ng/L (n = 2847;
age, 6 years and older). There was little difference
between genders and different age groups (CDC, 2013).
In Austria, values of < 1 ng Pt/L urine were reported
for unexposed people (number of subjects not given)
(Adeloju et al., 1990). In the United Kingdom, office
 50 Platinum
workers (n = 5) had 129 ng Pt/L in the blood and 113 ng
Pt/g creatinine in the urine (Farago et al., 1998). Iavicoli
et al., (2004a) reported a mean urinary platinum con-
centration of 4.56 ng/L in 58 people from Italy. They
found a statistical difference between female and males
(4.09 vs. 5.77 ng/L; P = 0.004). Subjects older than 40
years of age (n = 28) showed statistically significantly
higher mean platinum concentrations in the urine than
those of younger colleagues (n = 21; P = 0.03). Four years
later, they reported a mean urinary concentration of
1.86 ng/g creatinine (median, 1.03 ng/g) in 55 control
subjects from Rome (Iavicoli et al., 2007). No statistically
significant difference in mean platinum concentrations
was observed between the urine of male (5.47 ng/L)
and female (5.13 ng/L) subjects (n = 25 for each) aged
between 20 and 68 years (Spezia et al., 2005). In Buda-
pest and Vienna, platinum concentrations in the urine
of adult inhabitants without occupational exposure
were on average 10.1 ± 8.8 and 3.7 ± 4.3 ng/g creatinine
(n = 100), respectively (Záray et al., 2004). In France,
five control subjects had platinum concentration in the
urine of < 1.5 ng/L (Konate et al., 2011). In the urine of
urban children in Italy, platinum concentrations were
0.9 ± 1.1 ng/g creatinine; these were not associated with
traffic density in the area of residence (Caroli et al., 2001).
In China, the reported average level was 16.3 ng/L
(n = 5) (Hu et al., 2005). Regional mean serum platinum
concentrations in Italy were 7.76 ± 0.23 ng/L in Umbria
and 7.04 ± 0.21 ng/L in Calabria (Bocca et al., 2010).
The median serum platinum concentration in
­German workers in a catalyst plant who worked out-
side the catalyst building was 6.35 ng/L (range, < 5.0-
42.1 ng/L; number of subjects not given) (Merget et al.,
1999). In Italy, the blood platinum level was 10 ± 2 ng/L;
the urine level was 5 ± 0.1 ng/L; and the level in hair
was 50 ± 8 ng/kg (n = 25) (Petrucci et al., 2005).
Liver platinum concentrations were 0.05-0.24 ng/g
(Zeisler and Greenberg, 1982). The platinum concen-
tration in human breast tissue was < 0.05 ng/g (wet
weight), but higher levels in the range of 25-90 ng/g
were detected in the fibrin layer and in fat tissue
from two patients with breast prostheses (Flassbeck
et al., 2003). Platinum concentrations in women with
silicone breast implants were 568  ± 
74.77  pmol/L
(111 ± 15 ng/L; n = 9) in whole blood, 1.77 ± 0.847 μg/g
creatinine (n = 10) in urine, 2.13 ± 2.984 ng/g (n = 9) in
hair, 0.88 ± 0.335 ng/g (n = 9) in nails, 1.90 ± 1.691 ng/g
(n = 9) in sweat, and 1.09 ± 0.316 μg/L (n = 6) in breast
milk. (Lykissa and Maharaj, 2006).
5.3  Biological Monitoring
No validated methods are available for the effective
monitoring of platinum compounds.
1133
Environmental exposure to platinum cannot be
reliably assessed by biomonitoring because leach-
ing from dental devices is a much more important
source of platinum than environmental exposure
(Becker et al., 2003). For the biological monitoring
PtCl4 > Pt(SO4 )2 4H2 O > PtCl2 > PtO2 of exposure to
platinum in occupational settings, blood, serum, and
urine specimens have all been used. Information from
studies in which reliable analytical methods are used is
given in Table 2. Although the concentrations of plati-
num generally seem to be higher when the exposure is
high (Petrucci et al., 2005), no quantitative correlation
between air platinum concentration and platinum con-
centration in biological fluids has been reported; thus,
quantitative estimates of occupational exposure cannot
be derived from biological monitoring—which is thus
limited to the identification of populations exposed at
work. In a small prospective study, concentrations of
platinum in plasma were not predictive of the devel-
opment of platinum sensitivity (Merget et al., 2002).
The best separation of different exposure groups
was achieved from an analysis of urine from workers
at a catalyst production factory (Petrucci et al., 2005);
thus, urine platinum measurements are likely to pro-
vide the best starting point for the development of a
validated biomonitoring system for platinum and plat-
inum compounds.
On the other hand, elevated serum platinum con-
centrations have been reported among patients treated
with cisplatin (where exposures are much higher): 20
years after treatment, elevated serum platinum con-
centrations could still be observed in treated patients
(treated subjects, n = 61, 64.9 ± 24.5 ng Pt/kg plasma;
controls, n = 18, < 6 ng Pt/kg plasma) (Gietema et al.,
2000). Elevated urinary or blood platinum levels have
also been reported in nursing and pharmacy personnel
involved in anticancer treatments (Nygren and Lund-
gren, 1997; Pethran et al., 2003; Ensslin et al., 1997). The
exposure of personnel to anticancer drugs is largely
dependent on handling practices, protection, and the
use of safety hoods or alternative closed systems during
both the preparation and administration of cytostatics.
6  EFFECTS IN ANIMALS AND HUMANS,
AND DOSE-RESPONSE RELATIONSHIPS
Platinum is not an essential element for microbes,
plants, animals, or humans. Platinum readily com-
plexes in vitro with O-, N-, and S-containing ligands
such as amino-, carboxyl-, imidazole-, and sulfhydryl
groups in amino acids (NAS, 1977). Therefore, free
platinum ions would not be expected to exist in living
organisms.
 TABLE 2  Platinum Concentrations in the Blood/Urine of Workers in Different Industries
No. and Type
Exposure Group of Samples Result, Average Maximum or Range Reference

Catalyst production

Catalyst workersc 5, serum 30-290 ng/La Merget et al., 2002

Catalyst workersd ?, serum 13.6 ng/L (median) < 5.0-263 ng/L Merget et al., 1999
Catalyst workers, high exposureb,d 10, serum 80 ng/La < 500 ng/La Merget et al., 2000
Catalyst workers, low exposureb,d 30, serum 20 ng/La < 500 ng/La
Metal dissolution dept. 1 14, blood 70 ± 40 ng/L Petrucci et al., 2005
Metal dissolution dept. 2 8, blood 140 ± 80 ng/L
Coating of supports for catalytic ­converters 26, blood 380 ± 310 ng/L
Adsorption on the carrier 14, blood 170 ± 170 ng/L
Sampling 14, blood 140 ± 110 ng/L
Recovery of PGEs from exhausted 8, blood 240 ± 170 ng/L
catalytic converters
Preparation of solutions for coating 3, blood, serum B: 110 ng/L, S: 80 ng/L Petrucci et al., 2004
3; urine 405 ng/L
Coating of supports for catalytic 3, blood, serum B: 2900 ng/L, S: 1550 ng/L
converters 3, urine 2065 ng/L
Adsorption on the carrier 3; blood, serum B: 110 ng/L, S: 40 ng/L
3, urine 145 ng/L
Recovery of PGEs from exhausted 3, blood, serum B: 210 ng/L, S: 150 ng/L
catalytic converters 3, urine 130 ng/L
Platinum refinery and catalyst productionb 1-12 ng/g creatinine Schierl et al., 1998
Current high exposure 15, urine 170-6270 ng/g creatinine
Former high exposure (2-6 years 4, urine 10-170 ng/g creatinine
after exposure)
Occasionally exposed to low levels 3, urine 16-230 ng/g creatinine
Precious metal workers 7, blood 246 ± 91 ng/L 152-423 ng/L Farago et al., 1998
7, urine 470 ± 355 ng/g creatinine 210-1180 ng/ g creatinine
Traffic workers

Highway maintenance workers 10, blood 145 ± 90 ng/L 126-158 ng/L Farago et al., 1998
10, urine 58 ± 37 ng/g creatinine 22-135 ng/g creatinine
Traffic police officers 94, urine 4.56 ± 2.84 ng/L 0.28 -13.67 ng/L Iavicoli et al., 2004a
Tram drivers 64, urine 3.55 ± 5.42 ng/g creatinine 0.22-27.61 ng/g creatinine Iavicoli et al., 2007
Service station workers 26, blood 73.8 ng/L ± 77.9 ng/L 5-270 ng/L Chittori et al. 2005
Dental workers

Dental healthcare workers 1, serum 2120 ng/L Iavicoli et al., 2004b

19, serum < 5 ng/L
20, urine < 10 ng/L
Dental technicians 27, urine ∼30 ng/L maximum, 170 ng/L Begerow et al., 1999
Hospital workers

Nursing staff, pharmacists 6, blood 470 ± 310 ng/L Nygren and

Graduate nurses 13, blood 2200 ± 1700 ng/L ­Lundgren,
Staff nurses 12, blood 3800 ± 4000 ng/L maximum, 13300 ng/L 1997
31, urine 126 ± 92 ng/L
Nurses 3, urine 920-1300 ng/L Turci et al., 2002
Nurses and pharmacists 10, urine 10220 ± 7220 ng/L 600-23100 ng/L Venitt et al., 1984
Nurses 39, blood < 5 ng/L Pilger et al., 2000
Hospital personnel 14, urine 12.6 ± 10.8 ng/L (16.6 ± 15.5  Ensslin et al., 1994
ng/g creatinine)
39, urine < 1.8 ng/L
Nurses 13, urine 4.36 ± 5.61 ng/g creat Ensslin et al., 1997
One surgeon and one perfusioniste 2 × 1018, urine B: < 0.05 nmol/L (< 10 ng/L) Näslund Andréasson
2 × 1018, blood U: < 0.01 μg/L et al. 2010
Hospital personnel 7 urine < 1.5 ng/L < 5 ng/L Konate et al., 2011

B, blood; PGEs, platinum group elements; S, serum; U, urine.

aMedian and maximum values taken from a logarithmic diagram.
bSee Table 1.
cTime of sampling, 1990–1995.
dTime of sampling, 1994.
eTime of sampling, 2008.
 50 Platinum
6.1  Acute Toxicity
Metallic platinum has a low acute toxicity. Oral
administration of fine metallic platinum dust to rats
caused slight necrotic changes in the gastrointestinal
epithelium, granular dystrophy of hepatocytes, and
swelling in the epithelium of the convoluted renal
tubules, but with no lethal effects (IPCS, 1991). After
intrauterine application, platinum wire or foil caused
only local effects, which were considered to be due to
the physical presence of a foreign object in the uterus
(Barlow and Sullivan, 1982). The toxicity of orally
administered platinum compounds in rats decreased
in the order:
PtCl4 > Pt(SO4 )2 4H2 O > PtCl2 > PtO2
Thus, water-soluble platinum compounds are more
toxic than insoluble ones (Holbrook et al., 1975).
Platinum coordination complexes with chloride
ligands, when administered orally, are more toxic than
platinum salts (IPCS, 1991). After high doses of hexa-
chloroplatinic acid, H2[PtCl6], the kidney is the target
organ, with the cause of death being renal failure (Ward
et al., 1976). Nephrotoxicity is the major side effect of
cisplatin therapy (Bokemeyer et al., 1996; Ferrari et al.,
2005; Markman 2003; Taguchi et al., 2005). Severe neu-
rotoxicity has also been observed when cisplatin is
used in chemotherapy (Sastry and Kellie, 2005).
Platinum coordination complexes, including
(NH4)2[PtCl4] and Na2[PtCl6], but also Na2[Pt(OH)6],
[PtNH3]4Cl2, and [Pt(NO2)2(NH3)2], are strongly irritant
or corrosive when applied to the eye, and are irritants
or strong irritants to the skin; platinum(IV) chloride is
an irritant to the skin, whereas platinum(II) chloride
and platinum oxide are nonirritants (IPCS, 1991). No
data are available on the acute toxicity of PNPs in vivo.
PNPs did not cause any cytotoxicity in an MTT (cell
proliferation) assay RAW 264.7 macrophages even at
a concentration of 1000 μmol/L (Rehman et al., 2012).
6.2 Sensitization
An asthma-like disease caused by platinum com-
pounds was first described among workers in photo-
graphic studios in Chicago, USA; it was later reported
(called platinosis) in workers in platinum refineries and
their laboratories (Karasek and Karasek, 1911; Hunter
et al., 1945; Roberts, 1951); it is currently—albeit mis-
leadingly—most commonly known as platinum salt
sensitivity (IPCS, 1991). Symptoms include watering
of the eyes, sneezing, tightness of the chest, wheezing,
breathlessness, coughing, and (in some patients) skin
lesions, usually urticaria, and signs of mucous mem-
brane inflammation. Respiratory symptoms usually
1135
subside approximately 1 h after cessation of exposure.
The latency period from the first exposure to the first
symptoms has usually varied between 3 months and
3 years, but may be only a few weeks. Patients show a
positive reaction to challenge to platinum compounds
in skin prick tests and a positive bronchial challenge
test to H2[PtCl6] (Calverley et al., 1999; IPCS, 1991;
Merget et al., 1994; Pepys et al., 1972). Platinum-
­
exposed workers showed an increased prevalence of
bronchial reaction to cold air (Baker et al., 1990; Brooks
et al., 1990), but bronchial hyperresponsiveness to
methacholine was not consistently related to platinum
sensitivity (Merget et al., 1991, 1994, 1996, 1999, 2000). In
a follow-up study, it was shown that if the exposure of
workers who reacted positively to prick testing con-
tinued unabated, then 100% became symptomatic
(­
Calverley et al., 1995). Of patients with a positive
prick test, 2 out of 23 also showed a positive reac-
tion in patch test to H2[PtCl6] (Cristaudo et al., 2005).
The eczema described in early studies (Roberts, 1951)
is apparently unrelated to platinum exposure but is
instead caused by irritation from the strong acids and
alkalis used in the process. In contrast, urticaria may
be related to platinum, notably to splashes of chloro-
platinate solutions (Hughes, 1980). A type 4 reaction,
allergic contact dermatitis concomitant with a positive
patch test to hexachloroplatinate, has been described
in a patient exposed to platinum (and palladium and
gold) salts (Watsky, 2007).
In early studies (Roberts, 1951), the prevalence of
“platinosis” was 60-100% of those exposed, indicat-
ing that platinum is a very potent sensitizer. In a more
recent study (Niezborala and Garnier, 1996), > 30% of
the workforce developed platinum sensitivity within
3 years. In the South African registry of occupational
respiratory diseases (Hnizdo et al., 2001), exposure
to platinum compounds was the third most frequent
cause of occupational asthma (after latex and iso-
cyanates) and represented 12% of all asthma cases.
Siracusa et al., (2000) estimated the prevalence of occu-
pational rhinitis to be 43% in a platinum refinery, with
an asthma:rhinitis ratio of 1:1.6.
The risk of developing platinum salt sensitivity
increases with increasing exposure (Baker et al., 1990;
Bolm-Audorff et al., 1992; Calverley et al., 1995, 1999;
Cristaudo et al., 2005; Merget et al., 1988, 1999, 2000);
In the study that characterized exposure most exten-
sively (Merget et al., 2000), 13/115 workers became
sensitized to hexachloroplatinate during an average
follow-up of 33 months at an average exposure of
14 μg/m3 soluble platinum (“high exposure”). No sen-
sitization was observed in the groups with “constant
low” (average duration, 43 months) or “intermittent
low” (average, 6.6 μg/m3 soluble platinum) exposure
1136 Mirja Kiilunen, Antero Aitio, and Tiina Santonen
(average duration, 46 months). The risk of sensitiza-
tion also increased with time of exposure (Cristaudo
et al., 2005; Linnett and Hughes, 1999), and removal
from exposure or decrease of exposure was linked
to a decreased prevalence of respiratory symptoms
(­Merget et al., 1999, 2001).
Platinum dust has generally been considered to
be biologically inert and nonallergenic. No adverse
health effects have been reported from exposure to
platinum dust alone (Czerchak and Gromiec, 2001;
Gómez et al., 2002). Surveillance of newly employed
workers in a platinum company indicated that the pro-
portion of sensitized workers was high among those
exposed to chloroplatinates but nonexistent among
those exposed to tetraamine platinum dichloride (i.e. a
platinum coordination complex in which there are no
chloride ligands) (Linnett and Hughes, 1999; Steinfort
et al., 2008). Among workers sensitized to platinum,
the potency of different platinum complexes to induce
positive skin prick tests consistently decreased in the
order:
(NH4 )2 [PtCl6 ] ≅ (NH4 )2 [PtCl
[ 4 ] > CS2 [PtNO
] 2 Cl3 ]
> CS2 [Pt(NO2 )2 Cl2 ] > CS2 Pt(NO2 )3 Cl > K2 [Pt(NO2 )4 ]
with the last compound being inactive. Other complexes
with strongly bound ligands, such as [Pt(NH3)4]Cl2
and [Pt(thiourea)4]Cl2, were also inactive. Complexes
containing amine (and chlorine) showed the same
general pattern, with important difference being that
the dichlorocomplexes (cis- and trans-[Pt(NH3)2Cl2]),
which are neutral, were completely inactive. When the
chlorine ligand was replaced by bromine, the activity
decreased, but was not abolished (Cleare et al., 1976).
Positive reactions to platinum in skin tests have not
been described among people treated with platinum
chemotherapeutic drugs, but sensitivity reactions,
including anaphylactic shock, are a well-known poten-
tial side effect of cisplatin and other platinum-contain-
ing chemotherapeutic agents (Basu et al., 2002; Lim
et al., 2004; Shepherd, 2003; S ­ liesoraitis and Chikhale,
2005; Thomas et al., 2003; Watanabe et al., 2005; Win-
dom et al., 1992; Zorzou et al., 2005; Zweizig et al.,
1994; Makrilia et al., 2010).
The mechanism of platinum salt sensitivity is likely
to be a type 1, immunoglobulin E (IgE)-mediated
response. It is believed that platinum salts acting as
haptens can combine with serum proteins, probably
through sulfhydryl and methionine groups, to form
the complete antigen (Cromwell et al., 1979; Merget
et al., 1994; Schultze-Werninghaus et al., 1978). Periph-
eral blood monocytes from symptomatic workers (who
react positively in prick tests), showed an increased
frequency of CD3+ lymphocytes for Vα2a+, Vβ11+,
and Vβ21.3+ T cells and showed elevated proliferation
responses to sodium hexachloroplatinate in vitro
(Raulf-Heimsoth et al., 2000).
An increased level of total IgE has been dem-
onstrated in the serum of patients diagnosed with
platinum sensitivity (Baker et al., 1990; Brooks et al.,
1990; Bolm-Audorff et al., 1992; Calverley et al.,
1999; ­Cromwell et al., 1979; Merget et al., 1988, 1994;
­Murdoch et al., 1986). However, the increases in total
IgE have generally been rather small and there is a
marked overlap with the values in nonsensitized ref-
erents (Baker et al., 1990; Brooks et al., 1990; Calverley
et al., 1999; Cromwell et al., 1979; Merget et al., 1988,
1994; Murdoch et al., 1986). In some studies, workers
with work-related symptoms of platinum sensitivity
have had elevated concentrations of platinum-specific
IgE in their blood (Bolm-Audorff et al., 1992; Brooks
et al., 1990; Cromwell et al., 1979; Merget et al., 1988,
1999; Murdoch et al., 1986), but not all studies have
reported this association (Calverley et al., 1999). More-
over, in some studies there is an extensive overlap
between workers with positive and negative skin tests
to platinum (Cromwell et al., 1979; Merget et al., 1988;
Murdoch et al., 1986).
Tobacco smoking is an important contribu-
tory factor in the development of allergy to plati-
num compounds (Baker et al., 1990; Calverley et al.,
1995; Linnett and Hughes, 1999; Merget et al., 2000;
­Newman Taylor et al., 1999; Niezborala and ­Garnier,
1996; Venables et al., 1989), although this relationship
was only observed in some subgroups of exposed
workers in a recent study (Cristaudo et al., 2005).
Relative risks as high as 8.0 (95% CI, 2.6-25) for smok-
ers to develop platinum sensitivity at work have been
reported (Calverley et al., 1995). In a study with small
numbers of participants, smoking appeared to be
especially important as a predictor of platinum sen-
sitization when exposure is low: in a case-referent
study (Newman Taylor et al., 1999) among workers
exposed to ammonium hexachloroplatinate (usually
at concentrations of less than 2 μg/m3), the odds ratio
for platinum sensitization was 9.1 for the group in
whom the exposure was estimated to be “low,” and
3.1 in the “high”-exposure group. Although an early
study reported an association between atopy and plat-
inum sensitization (Hughes, 1980), and in two studies
a statistically nonsignificant excess relative risk was
reported for atopic persons to develop platinum sensi-
tivity (Cristaudo et al., 2005; Venables et al., 1989), the
weight of evidence seems to be that atopic constitu-
tion is not related to a predisposition to platinum sen-
sitivity (Baker et al., 1990; Bolm-Audorff et al., 1992;
Calverley et al., 1999; Cristaudo et al., 2005; M ­ erget
et al., 2000; Niezborala and Garnier, 1996, ­Siracusa
et al., 2000).
 50 Platinum
Histocompatibility antigen (HLA) type DR3 was
more common and HLA DR6 less common among
workers sensitized to platinum than among matched
nonsensitized referents (Newman Taylor et al., 1999).
The difference was more marked in the group whose
exposure was considered low than among those who
were exposed to high Pt levels. Because the prevalence
of sensitization in early studies—reflecting high expo-
sures—was also very high, up to 100%, it is likely that
at high exposure levels, sensitization will take place
independent of the HLA phenotype. The odds ratio for
the presence of DR3 was rather low (1.6 for the high-
exposure group and 2.3 for the low-exposure group),
and thus the attributable fraction for HLA DR3 is low.
In contrast, the odds ratio for the presence of HLA DR6
was 0.6 for high-exposure group and 0.1 for the low-
exposure group—denoting a high attributable fraction
at low exposures. It should be noted, however, that the
point estimates have very large 95% CIs (e.g. 0.02-1.1
for HLA DR6, low-exposure group).
There is currently no evidence of adverse health
effects from platinum in the general environment. In a
series of 749 patients with eczema and 51 with urticaria
from the Rome area (exposed to environmental plati-
num), no positive patch or prick test toward platinum
was observed (Santucci et al., 2000).
In C57 mice, a single subcutaneous injection of hexa-
chloroplatinates, tetrachloroplatinates, and cisplatin,
but not of [Pt(NH3)4]Cl2, induced increased weight
and cellularity in the popliteal lymph node (Schuppe
et al., 1992, 1997). An enhanced reaction was observed
after preceding treatment with [PtCl6]2−, indicating a
specific sensitization reaction. The reaction was con-
sidered to require T cells because nude mice lacking
T cells did not show the same reaction. Differences
in reactivity between inbred mouse strains indicate a
genetic susceptibility to platinum sensitivity. Sodium
hexachloroplatinate also produced a positive response
in an auricular lymph node assay and a mouse ear-
swelling test for contact hypersensitivity. However,
the concentrations needed for positive reactions were
high enough to also cause an irritant reaction (Schuppe
et al., 1997). In an abstract, it was reported that PtO2 and
PtCl2 did not elicit an immune response in the mouse
popliteal lymph node assay (Schuppe et al., 1993).
6.3  Pulmonary Effects of Platinum
Nanoparticles
Inflammatory responses relevant for chronic lung
diseases such as asthma and chronic obstructive pul-
monary disease, have been studied in mice follow-
ing exposure to PNPs. Park et al., (2010b) exposed
mice endotracheally to PNPs and saw induction of
1137
proinflammatory cytokines [interleukin-1 (IL-1),
tumor necrosis factor (TNF-α), and IL-6], cytokines
involved in T helper type 1 (Th1), Th2, and Th0 differ-
entiation, and transforming growth factor beta (TGF-β)
in bronchoalveolar lavage. These changes were accom-
panied by macrophage and neutrophil infiltration into
lung tissue (Park et al., 2010b). On the other hand,
polyacrylate-stabilized PNPs were suggested to act
as antioxidants, attenuating inflammatory responses
caused by e.g. tobacco smoke (Onizawa et al., 2009).
These anti-inflammatory effects have been proposed
to be attributed to their downregulation of the nuclear
factor-kappa-B (NF-κB) signaling pathway in macro-
phages (Rehman et al., 2012).
6.4  Carcinogenicity, Mutagenicity, and
Reproductive Effects
There are no data available on the carcinogenicity
of metallic platinum or its halogenated complexes in
humans or experimental animals, other than for cispla-
tin. The International Agency for Research on Cancer
has concluded, on the basis of sufficient evidence of
carcinogenicity in experimental animals, inadequate
evidence in humans, and supporting evidence from
other relevant data, that cisplatin is probably carcino-
genic to humans (group 2A carcinogen) (IARC, 1981;
1987).
Cisplatin is mutagenic in a variety of different test
systems (IARC, 1981, 1987; IPCS, 1991; Lantzsch and
Gebel, 1997; Nersesyan et al., 2003; Overbeck et al.,
1996; Silva et al., 2005; Uno and Morita, 1993; Socaciu
et al., 1996); similarly, other platinum cytostatic drugs
have been shown to be genotoxic (IPCS, 1991; Lantzsch
and Gebel, 1997; Nersesyan et al., 2003; Overbeck et al.,
1996; Silva et al., 2005).
In addition, platinum complexes and salts that
do not share the planar structure have been shown
to react with DNA, induce mutations in Salmonella
typhimurium, Escherichia coli, Bacillus subtilis, or L 5178
mouse lymphoma cells, or induce chromosomal dam-
age in CHO cells, V79 cells, or human lymphocytes
in vitro (Bunger et al., 1996; Butour et al., 1997; Gebel
et al., 1997; IPCS, 1991; Kanematsu et al., 1990; Lantzsch
and Gebel, 1997; Migliore et al., 2002). No genotoxicity
has been reported in in vivo studies (IPCS, 1991).
In an HPRT gene mutation assay in Chinese ham-
ster ovary cells, the approximate relative mutagenic
activity of cis-[Pt(NH3)2Cl2], K[Pt(NH3)Cl3], and
[Pt(NH3)3]Cl]Cl was 100:9:0.3, whereas the mutagenic-
ity of K2[PtCl4] and trans-[Pt(NH3)2Cl2] were close to
the spontaneous mutation frequency (but increased
in a concentration-dependent fashion). No mutagenic
activity was observed for [Pt(NH3)4Cl2 (IPCS, 1991).
1138 Mirja Kiilunen, Antero Aitio, and Tiina Santonen
Cisplatin binds to metallothionein (MT), and MT
sequestration may contribute to cisplatin resistance
(Hagrman et al., 2003). Transfection of the gene encod-
ing metallothionein increases cisplatin resistance in
an osteosarcoma cell system (Kasahara et al., 1991;
Vandier et al., 2000). No information is available on the
reproductive toxicity of platinum compounds other
than cisplatin: maternal doses in the order of the LD50
of cisplatin (13 mg/kg) caused a high rate of mortality
in the pups, but survivors did not show teratogenicity
(IARC, 1981).
Intraperitoneal administration of platinum chloride
(9-18 mg/kg; approximately 0.25-0.5 of the LD50) to
male rats resulted in decreased testicular DNA synthe-
sis; this effect, however, was more pronounced in the
spleen, liver, and kidneys (Fisher et al., 1975).
Hydrogen hexachloroplatinate at concentrations up
to 1000 μM did not affect sperm motility, membrane
integrity, or viability after 3 h (Kohn et al., 1995). Sperm
mobility was markedly reduced when spermatozoa
were treated with 1000 μM sodium hexachloroplati-
nate or tetraammineplatinum(II) chloride solutions.
An acrosome reaction was observed at concentrations
affecting sperm motility or lower (Eberl et al., 2000;
Kohn et al., 1995). Metallic platinum did not inhibit the
motility or oxygen consumption of human spermato-
zoa (Holland and White, 1980).
PNPs induced DNA strand breaks in human colon
cancer cells, apparently after the cellular uptake of
the particulate form and transfer of solubilized plati-
num to the nucleus (Gehrke et al., 2011). Weakly posi-
tive results were also observed in the Ames test in S.
typhimurium strain TA100 after exposure to iron-PNPs
but not in other strains or in E. coli (Maenosono et al.,
2007). Park et al., (2010b) studied the developmental
toxicity of PNPs after oral administration of PNPs to
mice at the doses of 0.25, 0.5, and 1 mg/kg during pre-
mating, gestation, and lactation periods. PNP exposure
did not result in maternal or fetal toxicity, but increased
mortality and decreased infant growth was observed
during the lactational period (Park et al., 2010b).
7  RISK ASSESSMENT
The main health effect of platinum compounds
is sensitization. The allergenic potency of platinum
compounds seems to be limited to coordination com-
plexes containing halogen ligands as leaving groups,
with hexa- and tetrachloroplatinates being the most
potent sensitizers. Neutral coordination complexes
such as diamminedichloroplatinum do not seem to
be allergenic. The incidence of platinum sensitivity
has been very high among exposed worker groups,
but has been shown to decrease with decreasing
exposure. Smokers have a higher risk of platinum
sensitization.
No adverse effects have been reported from envi-
ronmental exposure to platinum, but concentrations of
platinum are continuously increasing, mainly from the
use of platinum in automotive catalyzers.
Uptake from platinum-containing noble metal
dental alloy restorations is an important source of
platinum; health effects from this exposure have not,
however, been reported.
At pharmacological doses, cisplatin causes nephro-
toxicity. Cisplatin is mutagenic in several test systems
and is considered likely to be carcinogenic in humans.
Although it is clear that the major population at risk for
carcinogenicity is treated patients, oncological nurses
may also be exposed to cisplatin unless they adhere to
appropriate work practices. Limited data are available
on the toxicity of PNPs despite their increasing use in
different applications.
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